ABSTRACT Thereisacriticalneedtodevelopnoveltherapiesforheadandnecksquamouscellcarcinoma(HNSCC).The incidence of HPV-related HNSCC is rapidly rising in the United States and other countries around the world, while tobacco-related HNSCC remains an aggressive disease with poor prognosis and limited therapeutic options. Worldwide, HNSCC accounts for over 600,000 cases annually and is a leading cause of cancer mortality in developing countries. A majority of HNSCC patients present initially with locally or locoregionally advanced disease, yet these patients largely succumb to locally recurrent disease. Gene expression profiling and modeling strongly support a critical role for inflammation in HNSCC initiation and progression. Immune therapy holds promise for the treatment of HNSCC, as the immunotherapeutic agent nivolumab (anti-PD-1) recently demonstrated clinical activity in a small percentage of patients with recurrent/metastatic HNSCC. However, these findings suggest that HNSCC patients would be excellent candidates for novel immune therapeutics that could target resistance to anti-PD-1. We have found that PI3K? in immune suppressive Tumor Associated Macrophages (TAMs) promotes tumor immune suppression and resistance to checkpoint inhibitorsinmousemodelsofHNSCC.GeneticorpharmacologicalinactivationofPI3K?, butnotofotherPI3K isoforms, repolarized TAMs toward a pro-inflammatory, anti-tumor phenotype and synergized with checkpoint inhibitors to activate memory T cells and eradicate HNSCC tumors. Our studies indicate that PI3K? inhibitors, such as the investigational agent IPI-549, may be valuable immune oncologic agents to treat and monitor HNSCCpatientoutcomes.OurstudiesalsoidentifiedanovelPI3K?-drivensignatureofimmunesuppression- that predicts decreased survival in HNSCC patients. We propose to test the hypothesis that this PI3K?- mediated signature of immune suppression can be used to monitor therapeutic responses to PI3K? inhibitors. WewillalsotestthehypothesisthattherapeuticstrategiesthatblockPI3K?-mediatedimmunesuppressionwill synergize with T cell targeted therapeutics to improve outcomes in HNSCC patients. The specific aims of this proposal are 1) To Identify the mechanisms by which PI3K? inhibitors synergize with anti-PD-1 to promote T cellrecruitmentandactivationinvivo,usingmousemodelsofHPV+andHPV-carcinogen-inducedHNSCC,2) To determine the effect of the PI3K? inhibitor IPI-549 on tumor immune responses in patients with resectable HNSCC, 3) To evaluate biomarkers of immune response in recurrent/metastatic HNSCC patients treated with IPI-549incombinationwithanti-PD-1.